5-(basic substituted)-10, 11-dihydro-11-oxo-5h-dibenzo[b, e][1, 4]diazepine compounds



United States Patent (BASH; SUBSTETUK'EB) 10,11 DHHYDRO 11- OXQ 5H DlfiENZO[b,e1[LMDIAZEPENE 661M- PQUNDS Jean Schmutz, Mural, near Bern, and Fritz Hunziker, Bern, Switzerland, assignors to Dr. A. Wander, S.A., Bern, Switzerland, a corporation of Switzerland No Drawing. Filed lune 29, 1962, Ser. No. 2%,156

ill Ciaims. (Ql. 26il-2393) This is a continuation in-part of our copending application, Serial No. 57,123, filed September 20, 1960, now abandoned.

This invention relates to novel heterocyclic nitrogencontaining compounds and a method of producing the same. More specifically, it relates to S-(basic substituted)-10,11-dihydro 11 0X0 5H dibenzo[b,e] [1,4]- diazepine compounds having the general Formula I:

X-Y (I) and salts, such as the acid addition salts or the quaternary ammonium salts thereof. In the above formula I the letter symbols have the following meanings: X represents a hydrocarbon chain containing between 2 and 3 inclusive carbon atoms; Y is a member selected from the class consisting of a dialkylamino radical having from 2 to 4 inclusive carbon atoms, pyrrolidino and piperidino radicals, and pyrroldino or piperidino radicals having one CH group thereof replaced by a member of the class consisting of O, NP, N(CH and -N(C H R is a member of the class consisting of hydrogen, methyl, ethyl and benzylrand R and R represent, interchangeably, a member of the class consisting of hydrogen, chlorine, trifluoromethyl, methyl, ethyl methoxy and ethoxy.

More specifically, the hydrocarbon chain containing 2 or 3 carbon atoms is the ethylene, propylene or isopropylene radical, and the dialkylamino radical having from 2 to 4 carbon atoms is the dimethylamino, diethylamino or methylethylamino group. The pyrrolidino or piperidino radical having one -(JH group thereof replaced by. a member of the group consisting of O', -NH, l(CH and N(C H is preferably the morpholino, piperazino, N methyl piperazino or N ethylpiperazino group.

As quaternary ammonium salts there may be mentioned, more especially, lower alkyl ammonium salts, for example, lower alkyl ammonium halides and sulphates, e.g., methyl, ethyl and propyl ammonium chlorides and sulphates.

These new basically substituted heterocyclic nitrogencontaining compounds according to the invention, including the bases per so as well as the non-toxic acid addition and quaternary ammonium salts th reof, are useful as parasympatholytics, antihistamines, spasmolytics, tranquilizers, psychic energizers and psycho stimulants.

The new compounds are obtained by cyclization or ring closure of the appropriate 0 amino o carbonydiphenylamines.

Patented dept. 22, 19nd Ice The starting materials to be subjected to ring closure to obtain the products in accordance with the present invention are represented by the following formula II:

t e NH C O R2 Rs BIT XY (H) in the above Formula II the letter symbols X, Y, R and R have the same meaning as identified above. R has one of the meanings of R above, and R is hydrogen or a low molecular weight alkyl radical, preferably the methyl, ethyl or propyl group.

The cyclization or ring closure of the o-amino-o-car boxy diphenylamines represented by Formula H to obtain the heterocyclic nitrogen-containing compounds of Formula I may be effected by heating the Formula ll starting material either alone or in the presence of a suitable inert solvent or reaction medium, e.g. xylene. When no solvent is employed, the heating is preferably carried out in vacuo. When a solvent is used, the solvent r is preferably distilled off at atmospheric pressure and the residue is then heated to dryness in vacuo. During the heating step, water or an alcohol is split 0E depending upon whether R is hydrogen or an alkyl group.

In the starting material of Formula II when R is hydrogen and R is an alkyl group, the ring closure may occur spontaneously to some extent. For example, in preparing the starting material by hydrogenation of an o-nitro o' carboxy diphenylamine to obtain the corresponding o-amino o'-carboxy diphenylamine, the latter compound may undergo concurrent ring closure, at least in part. However, in any case subsequent heating is desirable to complete the reaction. In particular when the starting material is a free acid(i.e. R is hydrogen), heating is necessary to complete the ring closure reaction.

As will be evident from the foregoing, the compounds of Formula I may be unsubstituted in the lO-position (i.e. R is hydrogen) or they may have an alkyl or benzyl substituent in the ill-position. Thus, if R of the starting material is an alkyl or benzyl group, then R of the final compound is identical with R of the starting material. in the case where R of the starting material is hydrogen, the cyclized final compound may be further reacted to obtain the desired alkyl or benzyl substituent in the 10- position. Preferably, the cyclized compound unsubstituted in the Iii-position is reacted with a compound of the formula R -Z wherein R is the desired alkyl or benzyl substituent and Z is acid radical, particularly the radical of a strong inorganic or organic acid such as a hydrohalogen acid or an organic sulfonic acid. The latter reaction may be effected by heating the R Z compound with the cyclized compound after previous or with simultaneous action of a suitable condensation agent, particularly the alkali metals, their hydrides, amides, or other organic alkali metal compounds, e.g. sodium amide, sodium hydride, phenyl sodium, tertiary butyl potassium, etc.

Those products of Formula 1 according to this invention, wherein R denotes methyl, ethyl or benzyl, can also be obtained by introducing the basic substituent X-Y in the S-pQsition of a corresponding 10-substi- ,form as solutions, suspensions or emulsions. they may be sterilized and/ or contain auxiliary substances,

. useful substances.

, pletely dried in vacuo.

tuted 10,11-dihydro 11-oxo-5H-dibenzo[b,e][1,41diazepine compound.

The starting materials used in this second process are represented by the following Formula 111:

Nf (III) In this formula, the letter symbols R and R have the same meaning as identified above, and R is a member of the class consisting of the methyl, ethyl and benzyl radicals. The Formula 111 compound is reacted with an ester of a basic alcohol having the formula ZXY, wherein X and Y have the meanings described above and Z represents an acid radical, particularly the radical of a strong inorganic or organic acid such as a hydrohalogen acid or an organic sulfonic acid. This reaction is preferably carried out by prior or concurrent metallization of the Formula ill compound using a suitable condensation agent, particularly the alkali metals, their hydrides, amides, or other organic alkali metal compounds, e.g.

.sodium amide, sodium hydride, phenyl sodium, or tertiary .butyl sodium.

The compounds of the Formula I type are strong bases which may readily be converted to water soluble, pharmaceutically active, non-toxic salts. For example, suitable inorganic acid addition salts include the hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates. Suitable organic acid addition salts may also be formed, e.g. the acetates, oxalates, malonates, succinates, malates, maleates, tartrates, or toluene sultonates. The monoand di-quaternary ammonium derivatives are also useful,

such derivatives being obtained, for example, by reacting the bases with a quaternizing agent such as a dialkylsulfate, an alkyl halide, or a sulfonic acid alkyl ester. The quaternary ammonium derivatives of the Formula I compounds may also be obtained by utilizing as starting ma teriels the quaternary ammonium derivatives of the Formula 11 compounds.

The new compounds are useful as medicaments, for example, in the form of pharmaceutical preparations, which contain the new compound or a salt thereof in admixture with a pharmaceutical organic or inorganic solid or liquid carrier suitable for enteral, parenteral or topical administration. For making up the preparation there can be employed substances which do not react with the new compounds such, for example, as water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, petroleum jelly.

cholesterol or another known carrier for medicaments.

The pharmaceutical preparations may be, for example, in the form of tablets, dragees, salves, creams or in liquid If desired,

such as preserving agents, stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They may also contain other therapeutically The preparations are obtained by the usual methods employed in formulating pharmaceutical dosage forms.

The following non-limiting examples will further illustrate the products and processes of the invention:

EXAMPLE 1 The Z-amino compound obtained by catalytic hydrogenation of 23.3 gm. of N-B-dimethylamino-ethyl-Z-nitrodiphenylamine-2'-carboxylic-acid ethyl ester was dissolved in 500 ml. of xylene. The xylene was distilled 011 within 4 hours at ordinary pressure and the residue was com By boiling with 200 ml. of l-n acetic acid in the presence of active carbon, filtering and thereafter making the substance alkaline with ammonia,

a basic resin was obtained which became crystalline on standing. The product was separated out, washed with Water and recrystallized from methanol-water 1:1, 9.7 gm. (53% of the theoretical) of S-fi-dimethylamino-ethyl-10, ll-dihydro-ll-oxo 5H-dibenzo[b,e] [1,4]diazepine being obtained in the form of solid granules with a melting point of 195 to 196 C.

EXAMPLE 2 The product obtained by catalytic hydrogenation of 7.35 gm. of N-{i-dimethylamino-ethyl 2 nitro-S-chlorodiphenylamine=2-carboxylic-acid methyl ester was treated as in Example 1. The cyclic base precipitated from the acetate was extracted with chloroform, and there were obtained 3.34 gm. (54% of the theoretical) of S B-dimethyla1nino-ethyl 7 chloro 10,11 dihydro-ll-oxo-SH-dibenzo[b,e] [1,4]diazepine in the form of reddish prisms with a melting point of 197 to 198 C. (from acetonepetroleum ether 1:3).

EXAMPLE 4 Using the same procedure as in Example 3, and from the hydrogenation product of 8.95 gm. of N-v-dimethylamino-propyl-2-nitro 5 chloro diphenylamine-2-carboxylic-acid methyl ester, there was obtained S-y-dimethylamino-propyl 7 chloro 10,11 dihydro ll-oxo-SH- dibenzo[b,e][1,4]diazepine, which could not be crystallized and which was isolated in the form of its hydrochloride with a decomposition temperature of 244 to 245 C. with a yield of 4.71 gm. (corresponding to 56% of the theoretical) from methanol-ether 1:3.

EXAMPLE 5 Using the same procedure as in Example 2, and from the hydrogenation product of 3.0 gm. of N-B-dimethylamino-ethyl-2-nitro-4-chloro-diphenylamine 2 carboxylic-acid ethyl ester, there were obtained 1.18 gm. (44% of the theoretical) of S-fl-dimethylamino-ethyl-8-chloro- 10,11-dihydro-11-oxo 5H dibenzo[b,e][1,41diazepine, having a melting point of 180 to 184 C. (from etherpetroleum ether 1:3).

EXAMPLE 6 Using the same procedure as in Example 2, and from the hydrogenation product of 6.42 gm. of N-y-dimethylamino propyl-2-nitro-4-chloro-diphenylamine-2-carboxylic-acid ethyl ester, there were obtained 2.20 gm. (42% 'of the theoretical) of 5-'y-dimethylamino-propyl-8-chloro- 10,11 dihydro-ll-oxo 5H dibenzo[b,e][1,4]diazepine 'with a melting point of 184 to 187 C. (from ether-petroleum ether 1:3).

EXAMPLE 7 Starting from N- -dimethy1amino propyl 2 benzylamino-diphenylamine-2'-carboxylic acid ethyl ester and using the same method as in Example 1, S-y-dimethylamino propyl-lO-benzyl 10,11 dihydro-ll-oxo-SH-dibenzo[b,e] [1,4]diazepine, boiling point 230 C./0.03 mm. Hg, was obtained in a yield of 47% of the theoretical.

EXAMPLE 8 By treating the product obtained according to Example 2 first with sodium amide in absolute dioxane and then with benzylchloride in benzene (both reagents in slight excess over the equivalent amount), and isolating the product in the usual way, the same product was obtained in Example 7 in a yield of 77% of the theoretical.

EXAMPLE 9 14.75 gm. of 10-methyl 10,11 dihydro-ll-oxo-SH-dibenzo[b,e][l,4]diazepine were boiled for 1 hour with 3.10grn. of powdered sodium amide in 120 ml. of absolute dioxane. After adding a concentrated benzenic solution of 13.3 gm.- of [3 -dimethylamino -ethyl chloride, which had been freshly prepared by decomposing an equivalent quantity of the hydrochloride with concentrated sodium hydroxide solution, taking up in benzene and drying the solution with potash, the mixture was boiled for 16 hours under reflux, whereupon the reaction mixture was concentrated to dryness and the residue distributed between ether and water. By exhaustive extraction of the basic fractions with dilute acetic acid, precipitation with ammonia, taking up the base in ether and working up the ethereal solution, there was obtained 16.4 gm. of S-fi-dimethylamino-ethyl-l-methyl-10,ll-dihydro- 1-1-oxo-5H-dibenzo[b,e][ 1,4]diazepine as a viscous resin with a boiling point of 186 to 188 C./0.03 mm. Hg.

3.43 gm. of this product, dissolved in 20 ml. of benzene, were treated with methyl iodide in slight excess to prepare the corresponding metho-iodide salt, which was obtained'in an amount of 1.98 gm, melting point 155 C. The salt is fairly hygroscopic and not reorystallizable. The metho-iodide was treated with silver chloride to prepare the corresponding metho-chloride salt, which could, however, not be obtained in a crystalline state.

The 10-methyl-l0,1l dihydro-l1-oxo-5II-dibenzo[b,e]- [1,4]diazepine used as the starting material was prepared by methylating 10-11-dihydro-11-oxo 5H dibenzo [b,e] [1,4]diazepine with tertiary butyl potassium and methyl iodide in dioxane-tertiary butanol. The yield was 94% of the theoretical, and the melting point 211 to 213 C. (from acetone-petroleum ether).

EXAMPLE Using the same procedure as in Example 9, in which potassium-tertiary butylate prepared by dissolving 2.70 gm. of potassium in 80 ml. of tertiary butanol was used instead of sodium amide in dioxane, there were obtained 11.1 gm. of the same product as in Example 9.

EXAMPLE 11 Using the same procedure as in Example 9, but employing 7.0 gm. of phenyl sodium instead of sodium amide, there were obtained 9.3 gm. of the same product as in Example 9.

EXAMPLE 12 Using the same procedure as in Example 9, but employing 1.8 gm. of sodium hydride instead of sodium amide, there were obtained 10.1 gm. of the same product as in Example 9.

EXAMPLE 13 From 32.9 gm. of 10-methyl-10,11-dihydro-11-oxo5lldibenzo[b,e][1,41diazepine and 30.2 gm. of 'y-dirnethylamino-propyl-chloride hydrochloride, there were obtained by using the same procedure as in Example 9, 39.6 gm. of 5- y-dimethylamino-propyl 10 methyl-10,11-dihydroll-oxo 5H dibenzo[b,e] [1,4]diazepine as a viscous oil with the boiling point 188 to 189 C./ 0.02 mm. Hg, which crystallized on standing for a fairly long time, with melting point 80 to 83 C. (from ether-petroleum ether).

3.35 gm. of this product, dissolved in 20 m1. of benzene, were treated with a benzenic solution of 1.36 gm. dimethyl-sulphate. By isolation of the product in usual manner the metho sulphat salt was obtained in an amount of 4.38 gm. in the form of sticky crystals, the melting point of which could not be determined because of very easy decomposition of the hygrocopic substance.

EXAMPLE 14 From 10.2 gm. of 10-benzyl-10,1l-dihydro-ll-oxo-SH- dibenzo[b,e][1,4]diazepine and 6.85 gm. of ,B-dirnethylamino-ethyl-chloride hydrochloride, there were obtained by using the same procedure as in Example 9, 10.1 gm. of well dried, crude S-B-dimethylamino-ethyl,l0-benzyl- 10,11 dihydro-l1-oxo-5H-dibenzo[b,e] [1,41diazepine as a resin. With 1 equivalent of hydrochloric acid, there was obtained a hydrochloride crystallizable from methanol-ether, containing 1 mol. of water of crystallization, melting between roughly 150 and 170 C. and rather sparingly soluble in water.

On adding methyl iodide in slight excess to a benzene solution of the base, the metho-iodide crystallizes with a melting point of 120 to 123 C. The salt is fairly hygroscopic and not recrystallizable.

The 10 benzyl-l0,1l-dihydro-l1-oxo-5H-dibenzo[b,e]- [l,4]diazepine used as the starting material was prepared, like the corresponding methyl compound, in accordance with the data given in Example 9 (with benzyl chloride instead of methyl iodide). The yield was 93% of the theoretical, and the melting point 151 to 154 C. (from acetone-petroleum ether).

EXAMPLE 15 From 20 gm. of 10-benzyl-10,1l-dihydro-ll-oxo-SH- dibenzo[b,e][1,41diazepine and 13.7 gm. of 'y-dimethylamino-propyl-chloride hydrochloride, there were obtained by using the same procedure as in Example 9, 20.5 gm. of 5-' dimethylamino-propyl 10 benzyl 10,11 dihydro- 11-oxo-51 I-dibenzo[b,e] [1,4]diazepine as a viscous resin with a boiling point of 230 C./0.03 mm. Hg. This product was identical with the products obtained according to Examples 7 and 8, respectively.

EXAMPLE 16 A 19.9 gm. quantity of crude N-S piperidinoethyl-Z- nitro-diphenylamine2-carhoxylic-acid ethyl ester were hydrogenated with 3 gm. of Raney nickel and 1 gm. of 5% palladium carbon in ml. of fine spirit at room temperature and at atmospheric pressure. The crude aminocarboxylic-acid ethyl ester, obtained after separation from the catal st by filtration and subsequent concentration, was refluxed with ml. of xylol for 16 hours. After adding 25 ml. of glacial acetic acid, the volatile fractions were driven oif with steam and the remaining aqueous solution purified with active charcoal. The base precipitated with ammonia was dissolved in chloroform, and the chloroform extracts, after Washing twice with Water, were dried over sodium sulphate and concentrated. The dry residue could be recrystallized from acetonepetroleum ether and ether-petroleum ether using active charcoal. There were obtained 12.1 gm. (75% of the theoretical) of 5/3-piperidino-ethyl-10,11-dihydroll-oxo- 5il-dibenzo[b,e] [1,41diazepine in the form of colourless flakes having a melting point of 184 to 186 C.

EXAMPLE 17 By proceeding as in Example 16, there were obtained from 23.8 gm. of crude N- -piperidino-propyl-Z-nitrodiphenylamine-2'-carboxylic-acid ethyl ester, 11.3 gm. (58% of the theoretical) of S-y-piperidino-pmpyl-10,11- dihydro 11 oxo-5Iil-dibenzo[b,e] [1,4]diazepine in the form of flakes having a melting point of 141 to 143 C. (recrystallized from ether-petroleum ether or from acetone-petroleum ether).

EXAMPLE 18 By proceeding as in Example 16, there were obtained from 20.9 gm. of crude N-B-morpholino-ethyl-2-nitrodiphenylarnine-2'-carboxy1ic-acid ethyl ester, 11.2 gm. (66% of the theoretical) of 5-;8-morpholino-ethyl-10,11 dihydro-ll-oxo-5H-dibenzo[b,e][1,4]diazepine in the form of massive granules having a melting point of 218 to 219 C. (recrystallized from acetone-ether).

'3 EXAMPLE 19 By proceeding as in Example 16, there were obtained from 5.77 gm. of crude N,B-(N'-methyl-piperazino-ethyl)- 2-nitro-diphenylamine-2-carboxylic-acid ethyl ester, 2.83 gm. (60% of the theoretical) of 55-(N-methyl-piperazino-ethyl) 10,11 dihydro 11 oxo-5H-dibenzo[b,e] [1,4]diazepine in the form of massive granules having a melting point of 159 to 161 C. (recrystallized from acetone-petroleum ether) EXAMPLE By proceeding as in Example 16, there were obtained from 13.5 gm. of crude N-B-dimethylamino-ethyl-Z-nitro- 4-methyl-diphenylamine-2'-carboxylic-acid ethyl ester, 4.3 gm. (40% of the theoretical) of S-B-dimethylarninoethyl-8-methyl 10,11 dihydro 11 o xo 5H dibenzo [b,e] [1,4] diazepine in the form of massive prisms having a melting point of 165 to 167 C. (recrystallized from ether-petroleum ether).

EXAMPLE 21 By proceeding as in Example 16, there were obtained from 9.8 gm. of N-fi-dimethylarnino ethyl 2 nitro-4- methoxy diphenylamine 2 carboxylic-acid ethyl ester, 4.4 gm. (56% of the theoretical) of S-B-dimethylaminoethyl-8-methoxy 10,11 dihydro 11 oxo-SH-dibenzo [b,e][1,4-]diazepine in the form of massive granules of melting point 157 to 159 C. (recrystallized from acetonepetroleum ether and from ether-petroleum ether).

EXAMPLE 22 The crude aminocarboxylic acid ester, obtained by reducing a 16.9 grn. quantity of crude N-B-dimethylaminoethyl-2-nitro-5'-chloro diphenylamine 2 carboxylicacid ethyl ester with zinc and hydrogen chloride gas in methanol, concentrating the reacting mixture and alkalizing it with ammonia in the usual 'way over an ethereal phase, was subjected to ring closure as described in Example 16. There were obtained 5.2 gm. (38% of the theoretical) of 3-ch1oro-5-,8-dirnethylamino-ethyl-10,11- dihydro-ll-oxo-5l-l-dibenzo[b,e][1,4]diazepine in the form of compact granules having a melting point of 194 -C. (recrystallized from acetone-ether and from acetonepetroleum ether).

EXAMPLE 23 Starting from N-[i-dimethylamino ethyl 2 methylamino-4-chloro-diphenylarnine 2' carboxylic-acid ethyl ester and using the same method as in Example 7, 11-5- dirnethylamino-ethyl-8-chloro-l0 methyl 10,11-dihydroll-oxo 5H dibenzo[b,e] [1,41diazepine, boiling point 179 C./0.01 mm, Hg, Was obtained in a yield of 57% of the theoretical.

EXAMPLE 24 Starting from N-B-dimethylamino ethyl 2 methylamino-4-methoxy diphenylamine 2 carboxylic-acid ethyl ester and using the same method as in Example 7, S-fi-dimethylamino ethyl 8 methoxy 10 methyl- 10,11-dihydro 11 oxo 5H dibenzo[b,e] [1,4]diazepine, boiling point 187 C./ 0.05 mm. Hg, which crystallized upon standing from acetone-petroleum ether, melting point 115 to 118 C., was obtained in a yield of 62% of the theoretical).

EXAMPLE 25 Starting from N-B-dimethylamino-ethyl 2 methylamino 4 methyl diphenylamine 2 carboxylic-acid ethyl ester and using the same method as in Example 7, S-B-dimethylamino-ethyl 8,10 dimethyl 10,11 dihydro-11-oxo-5H-dibenzo[b,e][1,4]diazepine, boiling point 169 to 170 C./0.05 mm. Hg, which crystallized upon standing from ether-petroleum ether, melting point 71 to 74 C., was obtained in a yield of 56% of the theoretical.

EXAMPLE 26 Starting from N-,8-dirnethylamino-ethyl 2 nitro-4- triiiucromethyl-diphenylamine 2 carboxylic-acid ethyl ester and using the same method as in Example 1, 5 8- dimethylamino ethyl 8 trifluorornethyl 10,11 dihydro-l1-oxo-5H-dibenzo[b,e] [1,4] diazepine was obtained in the form of its mono-hydrate, melting point to 172 C. (from ether-petroleum ether) in a yield of 58% of the theoretical.

The following compounds further illustrate the scope of the present invention:

5-,8- (N-methyl-piperazino-ethyl) -8-methoxy-10, 1 1- dihydo-l1-oxo-5H-dibenzo[b,e] 1,4] diazepine 5 -fi-pyrro1idino-ethyl-8-trifiucromethyl- 10,1 l-dihydro-l 1- oxo-5H-dibenzo[b,e] [1,4]diazepine 5 -,8-piperidino-cthyl-S-trifluorornethyl-1 0, 1 l-dihydro-l 1- oxo-5H-dibenzo[b,e] [1,41diazepine 5-fl-rnorpholino-ethyl-S-trifluoromethyl-10,1l-dihydro-lloxo-5H-dibenzo[b,e] [1,41diazepine 5 B-(N-methyl-piperazino-ethyl) -8-trifluoromethyl-10,1 1-

dihydro-l 1-oxo5H-dibenzo [b,e] [1,4] diazepine 2-chloro-5-B-dimethylamino-ethyl-10, 1 l-dihydro-l l-oxo- 5H-dihenzo [b,e] [1,4] diazepine Z-methyl-5-,8-dimethylamino-ethyl-10,1 l-dihydro-l 1-ox0- SH-dibenzo [b,e] [1,41diazepine Z-nethoxy-S-B-dimethylamino-ethyl- 10,1 l-dihydro-l 1- oxo-SH-dibenzo [b,e] [1,4] diazepine Z-trifiuoromethyl-S -B-dimethylamino-ethyl- 1 0,1 l-dihydro- 11-0xo-5H-dibenzo[b,e] [1,4] diazepine 2-chl0ro-5-'y-dimethylamino-propyll 0,1 l-dihydro-l 1- oxo-SH-dibenzo [b,e] [1,4] diazepine Z-methyl-S-y-dimethylamino-propyl-10, 1 l-dihydro-l 1- oxo-SH-dibenzo [b,e] [1,4] diazepine Z-rnethoxy-5- -dimethylamino-propyl-10, 1 l-dihydro-l 1- oxo-SH-dibenzo [b,e] [1,4] diazepine Z-trifluoromethyl-S-y-dimethylamino-propyL10,1 ldihydro-l l-oxo-SH-dibenzo [b,e] [1,4] diazepine 2-chloro-S-B-pyrrolidino-ethyl-10,1l-dihydro-ll-oxo-SH- dibenzo [b,e] [1,4] diazepine 2-rnethyl-S-B-pyrrolidino-ethyl-10,1 l-dihydro-l l-oxo-SH- dibenzo [b,e] [1,4] diazepine 2-methoxy-5-,8-pyrro1idino-ethyl-10,1l-dihydro-ll-oxo- SH-dibenzo [b,e] [1,4 diazepine Z-triflucromethyl-S -B-pyrro1idino-ethyl- 1 0,1 l-dihydro-l 1- 5 Idibenzo [b,e] [1,4 diazepine i chloro-S-B-piperidino-ethyl-10,1 l-dihydro-l 1-oxo-5H- dibenzo [b,e] [1,4] diazepine 2-methyl-5-,8-piperidino-ethyl-10,1l-dihydro-ll-oxo-SH- dibenzo [b,e] [1,41diazepine 2-meth0xy-S-B-piperidino-ethyl- 10, 1 l-dihydro-l l-oxo-SH- dibenzo[b,e] [1,4]diazepine Z-trifluoromethyl-S-fl-piperidino-ethyl-10,1 l-dihydro-l 1- oxo-SH-dibenzo [b,e] [1,4] diazepine Production of Tablets For the manufacture of tablets, the products of the present invention, preferably in the form of the hydrochlorides or of the maleates, can be mixed with lactose and granulated with water, 0.5% sodium alginate solution or 1% gelatin solution. The dried granulate can be compressed into tablets in the presence of about 5% of talcum, 5% of corn starch and 0.1% of magnesium stearate, having, for instance, the following composition:

5 ,B-dimethylamino-ethyl-B-chloro-1'0,1l-dihydro-l1- oxo 5H dibenzo [b,e] [1,4]diazepine hydrochlo ride 1 Lactose 144 Corn starch 8 Talcum 8 Magnesium stearate 0.2

These 0.161 gm. tablets possess antihistaminic action and can be given orally in appropriate indications, e.g. for the treatment of allergic conditions.

Production of Solutions Injectable solutions are obtained, for example, by dissolving in bidistilled Water the products of the present invention in the form of their hydrochlorides or other salts and by adding sodium chloride or glucose until isotonic concentration is reached. The solutions are filtered free of germs, filled into ampoules and sterilized for 30 minutes at 120 C. in the autoclave. In this way, for example, injectable solutions of the following composition can be manufactured:

Mg. 5 ,9 dimethylamino-ethyl-8-methyl-10,11-dihydro- 11 oxo SH-dibenzo [b,e] [1,4] diazepine hydrochloride 1 Sodium chloride 41.5

Bidistilled water, up to 5 ml.

These solutions can be administered by intravenous injection, for example, for the treatment of allergic conditions.

Production of Suppositories Suppositories are obtained, for example, by grinding to a fine powder the products of the present invention in the form of bases and salts, by mixing intimately with a molten suppository mass (e.g. Oleum Cacao, Witten mass and the like) if necessary in the presence of parafiin oil, by pouring the mixture into moulds and by allowing to cool at low temperature. In this way, for example, suppositories of the following composition can be manufactured:

5-;3-dirnethylamino-ethyl-S-methoxy-10,1 l-dihydro- 11-oxo-5H-dibenzo [b,e] [1,4] diazepine 1 Parafiin oil 95 Oleum Cacao 210 10 The suppositories are administered, for example, in allergic affections.

We claim: 1. A compound selected from the group consisting of (A) S-(basic substituted)-l0,ll-dihydro-ll-oxo-SH-dibenzo[b,e] [1,4]diazepine derivatives of the formula 11% 9 N-C o 1 8 1o 11 2 R? R. 7 ,5 3 e f 4 wherein X is a member of the class consisting of ethylene, propylene, and isopropylene; Y is a member of the class consisting of dimethylamino, diethylamino, methylethylamino, pyrrolidino, piperidino, morpholino, piperazino, N-methylpiperazino, and N-ethylpiperazino; R is a member of the class consisting of hydrogen, methyl, ethyl and benzyl; and R and R represent, interchangeably, a member of the class consisting of hydrogen, chlorine, trifluoromethyl, methyl, ethyl, rnethoxy and ethoxy; and the non-toxic therapeutically useful acid addition salts and the non-toxic pharmaceutically acceptable quaternary ammonium salts selected from the group consisting of lower alkyl ammonium halides, lower alkyl ammonium sulphates, and lower alkyl ammonium sulphonates of (A).

2. 5-,8-dimethylamino ethyl-10,1l-dihydro-ll-oxo-SH- dibenzo [b,e] [1,4]diazepine.

3. S-y-dimethylamino-propyl- 1 0,1 1-dihydro-11-oxo-5H- dibenzo [b,e] [1,4] diazepine.

4. S-B-dimethylamino-ethyl-7-chloro-10,1 l-dihydro-l 1- oxo-SH-dibenzo [b,e] [1,4] diazepine.

5. S-B-dimethylamino-ethyl-8-chloro-10,1 l-dihydro-l 1- oxo-SH-dibenzo [b,e] [1,4] diazepine.

6. 5 -fl-dimethylamino-ethyl-S-methyl- 10,1 1-dihydro-1 1- oxo-5H-dibenzo[b,e] [1,4] diazepine.

7. S-fl-dimethylamino ethyl-8-methoxy-10,11-dihydro- 1l-oxo-5H-dibenzo[b,e] [1,4] diazepine.

8. S-Qdimethylamino ethyl-8-trifluoromethyl-10,11- dihydro-l1-oxo-5H-dibenzo[b,e] [1,4] diazepine.

9. S-Q-dimethylamino-ethyl l0-methyl-10,11-dihydro- 1 1-oxo-5H-dibenzo[b,e] [1,4] diazepine.

10. 5- -dimethylamino propyl-10-methyl-l0,1l-dihydro-l1-oxo-5-dibenzo[b,e] [1,4] diazepine.

References Cited in the file of this patent UNITED STATES PATENTS 2,852,510 Hotfmann et a1. Sept. 16, 1958 2,852,528 Hoifmann Sept. 16, 1958 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF (A) 5-(BASIC SUBSTITUTED)-10,11-DIHYDRO-11-OXO-5H-DIBENZO(B,E)(1,4) DIAZEPINE DERIVATIVES OF THE FORMULA 